Triple reuptake inhibitors and methods of their use

ABSTRACT

Provided herein are bicyclic compounds and methods of synthesis thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders. Compounds provided herein inhibit re-uptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine (e.g., from the synaptic cleft) and modulate one or more monoamine transporter. Pharmaceutical formulations containing the compounds are also provided.

This application claims priority to U.S. Provisional Application No.61/138,062, filed Dec. 16, 2008, the entirety of which is incorporatedherein by reference.

1. FIELD

Provided herein are compounds useful as triple reuptake inhibitors,compositions comprising the compounds, and methods of their use.

2. BACKGROUND

Monoamine neurotransmitters have been implicated in the body's responseto neurological disorders such as pain and depression. Norepinephrine(NE) and serotonin (5-HT) are monoamine neurotransmitters originating inthe brain and projecting diffusely throughout the central nervoussystem. 5-HT and NE are reported to be involved in modulating paintransmission from the spinal cord to the brain and also governing thebody's moods and responses to stress.

Depression refers to an abnormal mood or a collection of symptoms thatconstitute a psychiatric disorder. Symptoms of depression includedisturbances in mood and affect (depressed mood, diminished interest andpleasure in activities), bodily function (weight and appetite changes,psychomotor disturbances, sleep disturbances, fatigue, and loss ofenergy), and cognitive processes (feelings of worthlessness and guilt,concentration difficulties, indecisiveness, thoughts of death orsuicide, and possibly delusions/hallucinations). These symptoms vary inintensity, duration and frequency and permit classification ofdepression into different classes. Other symptoms of major depressiveepisodes include crying spells, self-pity, hopelessness, irritability,brooding, diminished self-esteem, decreased libido, nihilism, socialwithdrawal, memory impairment, feelings of inadequacy, and pessimism.

It has been reported that electrical stimulation of certain brainregions releases 5-HT and NE, which are believed to produce an analgesiain both animals and humans. Conversely, it has been reported thatdepletion of serotonin in the rat results in an enhanced response topain. There also appears to be synergistic actions between NE and 5-HTin modulating pain sensation. Studies in the rat show that the analgesiafrom exogenously administered 5-HT can be blocked by depleting NE in thespinal cord.

Common antidepressants increase synaptic availability of biogenic aminesby blocking their major means of physiological inactivation, whichinvolves transport or reuptake into nerve terminals. Examples include“dual” action agents that inhibit the reuptake of both NE and 5-HT(e.g., venlafaxine and milnacipram), selective serotonin reuptakeinhibitors (SSRIs) (e.g., fluoxetine and sertraline), and norepinephrinereuptake inhibitors (e.g., Reboxetine). A major drawback to all of theseagents is the therapeutic lag associated with their use—patients musttake the drug for up to 3 weeks to achieve clinically meaningfulsymptomatic relief. Furthermore, a significant number of patients do notrespond to current therapies at all. For example, it is currentlyestimated that up to thirty percent (30%) of clinically diagnosed casesof depression are resistant to all forms of current drug therapy.Consequently, there is a significant need for effective treatments ofvarious neurological disorders.

3. SUMMARY

Provided herein are compounds of formula (I), or pharmaceuticallyacceptable salt or solvate thereof:

wherein X, Y, Z, m, and n are defined herein elsewhere. The compoundsare useful as “triple reuptake inhibitors.”Also provided herein arecompositions and dosage forms comprising compounds provided herein.Compositions and dosage forms provided herein may comprise one or moreadditional active ingredients.

Also provided herein are methods for the treatment, prevention, and/ormanagement of various neurological disorders using the compounds andcompositions provided herein. Neurological disorders that may betreated, prevented, and/or managed include, but are not limited to,depression (e.g., major depressive disorder, bipolar disorder),fibromyalgia, pain (e.g., neuropathic pain), sleep apnea, attentiondeficit disorder (ADD), attention deficit hyperactivity disorder (ADHD),restless leg syndrome, schizophrenia, anxiety, obsessive compulsivedisorder, posttraumatic stress disorder, seasonal affective disorder(SAD), premenstrual dysphoria, neurodegenerative diseases (e.g.,Parkinson's disease, Alzheimer's disease) and any other neurologicaldisorders described herein elsewhere. In addition, methods for thetreatment, prevention, and/or management of obesity or treatment ofsubstance abuse, dependency or addiction, including but not limited tonicotine and cocaine abuse, dependency or addiction are also providedherein.

In another embodiment, provided herein is a method of inhibiting bindingof a monoamine transporter ligand to a monoamine transporter, such asserotonin transporter, dopamine transporter and norepinephrinetransporter. The method comprises contacting the monoamine transporterand a compound of the invention. In an exemplary embodiment, themonoamine transporter ligand is a monoamine, such as serotonin, dopamineand norepinephrine.

Also provided herein is a method of inhibiting the activity of at leastone monoamine transporter, such as serotonin transporter, dopaminetransporter and norepinephrine transporter. The method comprisescontacting the monoamine transporter and a compound provided herein.

Also provided herein is a method of inhibiting uptake of at least onemonoamine, such as serotonin, dopamine and norepinephrine, by a cell.The method comprises contacting the cell with a compound of theinvention. In an exemplary embodiment, the cell is a brain cell, such asa neuronal cell or a glial cell.

4. BRIEF DESCRIPTION OF FIGURES

FIG. 1 illustrates the levels of tested compounds in brain following anoral administration at a dose of 10 mg/kg.

FIG. 2 illustrates the ratio of brain and plasma levels of the testedcompounds following an oral administration at a dose of 10 mg/kg.

FIG. 3 illustrates the effects of(3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole (“thetest compound”) on flinching responses. (V: Vehicle; 3: 3 mg/kg testcompound; 10: 10 mg/kg test compound; 30: 30 mg/kg test compound; and G:Gabapentine (100 mg/kg)).

5. DETAILED DESCRIPTION

5.1 Definitions

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may optionally be substituted with one or moresubstituents. The term “alkyl” also encompasses both linear and branchedalkyl, unless otherwise specified. In certain embodiments, the alkyl isa linear saturated monovalent hydrocarbon radical that has 1 to 20(C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6(C₁₋₆) carbon atoms, or branched saturated monovalent hydrocarbonradical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ alkyl groups are also referred as “lower alkyl.” Examplesof alkyl groups include, but are not limited to, methyl, ethyl, propyl(including all isomeric forms), n-propyl, isopropyl, butyl (includingall isomeric forms), n-butyl, isobutyl, t-butyl, pentyl (including allisomeric forms), and hexyl (including all isomeric forms). For example,C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbon radicalof 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbonradical of 3 to 6 carbon atoms.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted one or moresubstituents. The term “alkenyl” also encompasses radicals having “cis”and “trans” configurations, or alternatively, “E” and “Z”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkenyl groups include, but are not limited to, ethenyl, propen-1-yl,propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted one or moresubstituents. The term “alkynyl” also encompasses both linear andbranched alkynyl, unless otherwise specified. In certain embodiments,the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groups include, but arenot limited to, ethynyl (—C═CH) and propargyl (—CH₂C═CH). For example,C₂₋₆ alkynyl refers to a linear unsaturated monovalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated monovalenthydrocarbon radical of 3 to 6 carbon atoms.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic saturated bridged and/or non-bridged monovalenthydrocarbon radical, which may be optionally substituted one or moresubstituents as described herein. In certain embodiments, the cycloalkylhas from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12 (C₃₋₁₂),from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, andadamantyl.

As used herein, and unless otherwise specified, the terms “heteroalkyl,”“heteroalkenyl,” and “heteroalkynyl” refer to alkyl, alkenyl, andalkynyl, respectively, wherein one or more carbon atoms are replacedwith heteroatoms.

As used herein, and unless otherwise specified, the term “heteroatom”refers to any atom other than carbon or hydrogen. In some embodiments,the term “heteroatom” refers to N, O, S, Si, or P. In other embodiments,the term “heteroatom” refers to N, O, or S.

As used herein, and unless otherwise specified, the term “aryl” refersto a monocyclic aromatic group and/or multicyclic monovalent aromaticgroup that contain at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), orfrom 6 to 10 (C₆₋₁₀) ring atoms. Examples of aryl groups include, butare not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers tobicyclic or tricyclic carbon rings, where one of the rings is aromaticand the others of which may be saturated, partially unsaturated, oraromatic, for example, dihydronaphthyl, indenyl, indanyl, ortetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may alsobe optionally substituted with one or more substituents.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl. Incertain embodiments, both alkyl and aryl may be optionally substitutedwith one or more substituents.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Insome embodiments, the salt is formed from hydrochloric, hydrobromic,phosphoric, or sulfuric acid. In one embodiment, the salt is formed fromhydrochloride salt.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,or greater than about 97% by weight of one stereoisomer of the compoundand less than about 3% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of disease or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing,” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In specific embodiments, thesubject is a human.

As used herein, and unless otherwise specified, the term “monoaminetransporter ligand” refers to any compound, which binds to a monoaminetransporter. Ligands include endogenous monoamines, which are thenatural ligands for a given monoamine transporter as well as drugmolecules and other compounds, such as synthetic molecules known to bindto a particular monoamine transporter. In one example, the ligandincludes a radioisotope, such as tritium or is otherwise (e.g.,fluorescently) labeled. It is within the abilities of the skilled personto select an appropriate ligand for a given monoamine transporter. Forexample, known ligands for the dopamine transporter include dopamine andWIN35428, known ligands for the serotonin transporter include5-hydroxytryptamine (serotonin) and citalopram, and ligands for thenorepinephrine transporter include norepinephrine and nisoxetine.

As used herein, and unless otherwise specified, the term “neurologicaldisorder” refers to any condition of the central or peripheral nervoussystem of a mammal. The term “neurological disorder” includes, but isnot limited to, neurodegenerative diseases (e.g., Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatricdiseases (e.g., schizophrenia and anxieties, such as general anxietydisorder), and affective disorders (e.g., depression and attentiondeficit disorder). Exemplary neurological disorders include, but are notlimited to, MLS (cerebellar ataxia), Huntington's disease, Downsyndrome, multi-infarct dementia, status epilecticus, contusive injuries(e.g., spinal cord injury and head injury), viral infection inducedneurodegeneration, (e.g., AIDS, encephalopathies), epilepsy, benignforgetfulness, closed head injury, sleep disorders, depression (e.g.,bipolar disorder), dementias, movement disorders, psychoses, alcoholism,post-traumatic stress disorder and the like. “Neurological disorder”also includes any condition associated with the disorder. For instance,a method of treating a neurodegenerative disorder includes methods oftreating loss of memory and/or loss of cognition associated with aneurodegenerative disorder. An exemplary method would also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder. “Neurological disorder” also includes anydisease or condition that is implicated, at least in part, in monoamine(e.g., norepinephrine) signaling pathways (e.g., cardiovasculardisease).

As used herein, and unless otherwise specified, the term “affectivedisorder” includes depression, attention deficit disorder, attentiondeficit disorder with hyperactivity, bipolar and manic conditions, andthe like. The terms “attention deficit disorder” (ADD) and “attentiondeficit disorder with hyperactivity” (ADDH), or attentiondeficit/hyperactivity disorder (AD/HD), are used herein in accordancewith the accepted meanings as found in the Diagnostic and StatisticalManual of Mental Disorders, 4^(th) Ed., American Psychiatric Association(1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “depression”includes all forms of depression including, but not limited to, majordepressive disorder (MDD), bipolar disorder, seasonal affective disorder(SAD) and dysthymia. “Major depressive disorder” is used hereininterchangeably with “unipolar depression” and “major depression.”“Depression” may also includes any condition commonly associated withdepression, such as all forms of fatigue (e.g., chronic fatiguesyndrome) and cognitive deficits.

As used herein, and unless otherwise specified, the terms“obsessive-compulsive disorder,” “substance abuse,” “pre-menstrualsyndrome,” “anxiety,” “eating disorders” and “migraine” are used hereinin a manner consistent with their accepted meanings in the art. See,e.g., DSM-IV™. For example, the term “eating disorder,” as used herein,refers to abnormal compulsions to avoid eating or uncontrollableimpulses to consume abnormally large amounts of food. These disordersmay affect not only the social well-being, but also the physicalwell-being of sufferers. Examples of eating disorders include, but arenot limited to, anorexia nervosa, bulimia, and binge eating.

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. The term “pain,” asused herein, refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic peripheral neuropathic pain (see, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia. In addition, The term “pain” includespain resulting from dysfunction of the nervous system: organic painstates that share clinical features of neuropathic pain and possiblecommon pathophysiology mechanisms, but are not initiated by anidentifiable lesion in any part of the nervous system.

The term “somatic pain,” as used herein, refers to a normal nerveresponse to a noxious stimulus such as injury or illness, e.g., trauma,burn, infection, inflammation, or disease process such as cancer, andincludes both cutaneous pain (e.g., skin, muscle or joint derived) andvisceral pain (e.g., organ derived).

The term “neuropathic pain,” as used herein, refers to a heterogeneousgroup of neurological conditions that result from damage to the nervoussystem. The term also refers to pain resulting from injury to ordysfunctions of peripheral and/or central sensory pathways, and fromdysfunctions of the nervous system, where the pain often occurs orpersists without an obvious noxious input. This includes pain related toperipheral neuropathies as well as central neuropathic pain. Commontypes of peripheral neuropathic pain include diabetic neuropathy (alsocalled diabetic peripheral neuropathic pain, or DN, DPN, or DPNP),post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Centralneuropathic pain, involving damage to the brain or spinal cord, canoccur following stroke, spinal cord injury, and as a result of multiplesclerosis, and is also encompassed by the term. Other types of pain thatare meant to be included in the definition of neuropathic pain include,but are not limited to, pain from neuropathic cancer pain, HIV/AIDSinduced pain, phantom limb pain, and complex regional pain syndrome.

The term also encompasses the common clinical features of neuropathicpain including, but not limited to, sensory loss, allodynia (non-noxiousstimuli produced pain), hyperalgesia and hyperpathia (delayedperception, summation, and painful aftersensation). Pain is often acombination of nociceptive and neuropathic types, for example,mechanical spinal pain and radiculopathy or myelopathy.

As used herein, and unless otherwise specified, the term “acute pain”refers to the normal, predicted physiological response to a noxiouschemical, thermal or mechanical stimulus typically associated withinvasive procedures, trauma and disease. It is generally time-limited,and may be viewed as an appropriate response to a stimulus thatthreatens and/or produces tissue injury. The term also refers to painwhich is marked by short duration or sudden onset.

As used herein, and unless otherwise specified, the term “chronic pain”encompasses the pain occurring in a wide range of disorders, forexample, trauma, malignancies and chronic inflammatory diseases such asrheumatoid arthritis. Chronic pain may last more than about six months.In addition, the intensity of chronic pain may be disproportionate tothe intensity of the noxious stimulus or underlying process. The termalso refers to pain associated with a chronic disorder, or pain thatpersists beyond resolution of an underlying disorder or healing of aninjury, and that is often more intense than the underlying process wouldpredict. It may be subject to frequent recurrence.

As used herein, and unless otherwise specified, the term “inflammatorypain” is pain in response to tissue injury and the resultinginflammatory process. Inflammatory pain is adaptive in that it elicitsphysiologic responses that promote healing. However, inflammation mayalso affect neuronal function. Inflammatory mediators, including PGE₂induced by the COX2 enzyme, bradykinins, and other substances, bind toreceptors on pain-transmitting neurons and alter their function,increasing their excitability and thus increasing pain sensation. Muchchronic pain has an inflammatory component. The term also refers to painwhich is produced as a symptom or a result of inflammation or an immunesystem disorder.

As used herein, and unless otherwise specified, the term “visceral pain”refers to pain which is located in an internal organ.

As used herein, and unless otherwise specified, the term “mixed etiologypain” refers to pain that contains both inflammatory and neuropathiccomponents.

As used herein, and unless otherwise specified, the term “dual mechanismpain” refers to pain that is amplified and maintained by both peripheraland central sensitization.

As used herein, and unless otherwise specified, the term “causalgia”refers to a syndrome of sustained burning, allodynia, and hyperpathiaafter a traumatic nerve lesion, often combined with vasomotor andsudomotor dysfunction and later trophic changes.

As used herein, and unless otherwise specified, the term “central pain”refers to pain initiated by a primary lesion or dysfunction in thecentral nervous system.

As used herein, and unless otherwise specified, the term “hyperesthesia”refers to increased sensitivity to stimulation, excluding the specialsenses.

As used herein, and unless otherwise specified, the term “hyperpathia”refers to a painful syndrome characterized by an abnormally painfulreaction to a stimulus, especially a repetitive stimulus, as well as anincreased threshold. It may occur with allodynia, hyperesthesia,hyperalgesia, or dysesthesia.

As used herein, and unless otherwise specified, the term “dysesthesia”refers to an unpleasant abnormal sensation, whether spontaneous orevoked. In certain embodiments, dysesthesia include hyperalgesia andallodynia.

As used herein, and unless otherwise specified, the term “hyperalgesia”refers to an increased response to a stimulus that is normally painful.It reflects increased pain on suprathreshold stimulation.

As used herein, and unless otherwise specified, the term “allodynia”refers to pain due to a stimulus that does not normally provoke pain.

As used herein, and unless otherwise specified, the term “DiabeticPeripheral Neuropathic Pain” (DPNP), also called diabetic neuropathy, DNor diabetic peripheral neuropathy), refers to chronic pain caused byneuropathy associated with diabetes mellitus. The classic presentationof DPNP is pain or tingling in the feet that can be described not onlyas “burning” or “shooting” but also as severe aching pain. Lesscommonly, patients may describe the pain as itching, tearing, or like atoothache. The pain may be accompanied by allodynia and hyperalgesia andan absence of symptoms, such as numbness.

As used herein, and unless otherwise specified, the term “Post-HerpeticNeuralgia”, also called “Postherpetic Neuralgia (PHN)”, refers to apainful condition affecting nerve fibers and skin. Without being limitedby a particular theory, it is a complication of shingles, a secondoutbreak of the varicella zoster virus (VZV), which initially causeschickenpox.

As used herein, and unless otherwise specified, the term “neuropathiccancer pain” refers to peripheral neuropathic pain as a result ofcancer, and can be caused directly by infiltration or compression of anerve by a tumor, or indirectly by cancer treatments such as radiationtherapy and chemotherapy (chemotherapy-induced neuropathy).

As used herein, and unless otherwise specified, the term “HIV/AIDSperipheral neuropathy” or “HIV/AIDS related neuropathy” refers toperipheral neuropathy caused by HIV/AIDS, such as acute or chronicinflammatory demyelinating neuropathy (AIDP and CIDP, respectively), aswell as peripheral neuropathy resulting as a side effect of drugs usedto treat HIV/AIDS.

As used herein, and unless otherwise specified, the term “Phantom LimbPain” refers to pain appearing to come from where an amputated limb usedto be. Phantom limb pain can also occur in limbs following paralysis(e.g., following spinal cord injury). “Phantom Limb Pain” is usuallychronic in nature.

As used herein, and unless otherwise specified, the term “TrigeminalNeuralgia (TN)” refers to a disorder of the fifth cranial (trigeminal)nerve that causes episodes of intense, stabbing, electric-shock-likepain in the areas of the face where the branches of the nerve aredistributed (lips, eyes, nose, scalp, forehead, upper jaw, and lowerjaw). It is also known as the “suicide disease”.

As used herein, and unless otherwise specified, the term “ComplexRegional Pain Syndrome (CRPS),” formerly known as Reflex SympatheticDystrophy (RSD), refers to a chronic pain condition whose key symptom iscontinuous, intense pain out of proportion to the severity of theinjury, which gets worse rather than better over time. The termencompasses type 1 CRPS, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2 CRPS, in which thesyndrome is provoked by major nerve injury, and is sometimes calledcausalgia.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

As used herein, and unless otherwise specified, the term “convulsion”refers to a neurological disorder and is used interchangeably with“seizure,” although there are many types of seizure, some of which havesubtle or mild symptoms instead of convulsions. Seizures of all typesmay be caused by disorganized and sudden electrical activity in thebrain. In some embodiments, convulsions are a rapid and uncontrollableshaking during which the muscles contract and relax repeatedly.

5.2 Compounds

Provided herein are compounds of formula (1):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein:

-   in is 0, 1, or 2;-   n is 0, 1, or 2;-   X is hydrogen, (C₁-C₁₀)alkyl, (C₃-C₁₀)cycloalkyl,    (C₃-C₁₀)cycloalkyl-(C₁-C₁₀)alkyl, (C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl,    (C₁-C₁₀)alkoxy, 6 to 10 membered aryl, (6 to 10 membered    aryl)-(C₁-C₁₀)_(alkyl, —OR) ¹, heteroalkyl, heteroalkenyl, or    heteroalkynyl;-   Y and Z are each independently halogen, —CF₃, —CN, —NH₂, —NO₂,    dioxolano, (C₁-C₁₀)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkenyl,    (C₁-C₁₀)alkynyl, (C₁-C₁₀)alkoxy, (C₃-C₁₀)cycloalkoxy, or —OR²; or-   Y and Z, taken together, may form 5, 6, or 7 membered cycloalkyl;    and-   R¹ and R² are each independently hydrogen, (C₁-C₁₀)alkyl,    (C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl,    (C₃-C₁₀)cycloalkyl-(C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, 6 to 10 membered    aryl, 6 to 10 membered heteroaryl, (6 to 10 membered    aryl)-(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyl, or —SO₂-(6 to 10 membered    aryl).

In one embodiment, m is 0. In another embodiment, m is 1. In anotherembodiment, m is 2.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

In one embodiment, X is hydrogen. In another embodiment, X is(C₁-C₁₀)alkyl. In another embodiment, X is (C₃-C₁₀)cycloalkyl. Inanother embodiment, X is (C₃-C₁₀)cycloalkyl-(C₁-C₁₀)alkyl. In anotherembodiment, X is (C₁-C₁₀)alkenyl. In another embodiment, X is(C₁-C₁₀)alkynyl. In another embodiment, X is (C₁-C₁₀)alkoxy. In anotherembodiment, X is 6 to 10 membered aryl. In another embodiment, X is (6to 10 membered aryl)-(C₁-C₁₀)alkyl. In another embodiment, X is —OR¹. Inanother embodiment, X is heteroalkyl. In another embodiment, X isheteroalkenyl. In another embodiment, X is heteroalkynyl. In anotherembodiment, X is heterocycloalkyl.

In one embodiment where X is —OR¹, R¹ is hydrogen. In anotherembodiment, R¹ is (C₁-C₁₀)alkyl. In another embodiment, R¹ is(C₁-C₁₀)alkenyl. In another embodiment, R¹ is (C₁-C₁₀)alkynyl. Inanother embodiment, R¹ is (C₃-C₁₀)cycloalkyl. In another embodiment, R¹is (C₃-C₁₀)cycloalkyl-(C₁-C₁₀)alkyl. In another embodiment, R¹ is(C₁-C₁₀)alkoxy. In another embodiment, R¹ is 6 to 10 membered aryl. Inanother embodiment, R¹ is (6 to 10 membered aryl)-(C₁-C₁₀)alkyl. Inanother embodiment, R¹ is —SO₂(C₁-C₁₀)alkyl. In another embodiment, R¹is —SO₂-(6 to 10 membered aryl).

In one embodiment, Y is halogen. In another embodiment, Y is —CF₃. Inanother embodiment, Y is —CN. In another embodiment, Y is —NH₂. Inanother embodiment, Y is —NO₂. In another embodiment, Y is dioxolano. Inanother embodiment, Y is (C₁-C₁₀)alkyl. In another embodiment, Y is(C₃-C₁₀)cycloalkyl. In another embodiment, Y is (C₁-C₁₀o)alkenyl. Inanother embodiment, Y is (C₁-C₁₀)alkynyl. In another embodiment, Y is(C₁-C₁₀)alkoxy. In another embodiment, Y is (C₃-C₁₀)cycloalkoxy. Inanother embodiment, Y is —OR².

In one embodiment, Z is halogen. In another embodiment, Z is —CF₃. Inanother embodiment, Z is —CN. In another embodiment, Z is —NH₂. Inanother embodiment, Z is —NO₂. In another embodiment, Z is dioxolano. Inanother embodiment, Z is (C₁-C₁₀)alkyl. In another embodiment, Z is(C₃-C₁₀)cycloalkyl. In another embodiment, Z is (C₁-C₁₀)alkenyl. Inanother embodiment, Z is (C₁-C₁₀)alkynyl. In another embodiment, Z is(C₁-C₁₀)alkoxy. In another embodiment, Z is (C₃-C₁₀)cycloalkoxy. Inanother embodiment, Z is —OR².

In one embodiment, where Y and/or Z are —OR², R² is hydrogen. In anotherembodiment, R² is (C₁-C₁₀)alkyl. In another embodiment, R² is(C₁-C₁₀)alkenyl. In another embodiment, R² is (C₁-C₁₀)alkynyl. Inanother embodiment, R² is (C₃-C₁₀)cycloalkyl. In another embodiment, R²is (C₃-C₁₀)cycloalkyl-(C₁-C₁₀)alkyl. In another embodiment, R² is(C₁-C₁₀)alkoxy. In another embodiment, R² is 6 to 10 membered aryl. Inanother embodiment, R² is (6 to 10 membered aryl)-(C₁-C₁₀)alkyl. Inanother embodiment, R² is —SO₂(C₁-C₁₀)alkyl. In another embodiment, R²is —SO₂-(6 to 10 membered aryl).

In one embodiment, Y and Z together form a 5 membered cycloalkyl. In oneembodiment, Y and Z together form a 6 membered cycloalkyl. In oneembodiment, Y and Z together form a 7 membered cycloalkyl.

Any of the combinations of m, n, X, Y, Z, R₁ and R₂ are encompassed bythis disclosure and specifically provided herein.

In one embodiment, n is 1. In one embodiment where n is 1, m is 1 or 2.

In one embodiment, X is hydrogen. In another embodiment, X is(C₁-C₁₀)alkyl. In another embodiment, X is methyl. In anotherembodiment, X is ethyl.

In one embodiment, at least one of Y and Z are halogen. In anotherembodiment, Y and Z are both halogen. In another embodiment, Y and Z areboth chloride.

Specific examples include, but are not limited to, the followingcompounds, or pharmaceutically acceptable salt, solvate, orstereoisomers thereof:

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

5.2.1 Synthetic Schemes

Five and six-membered ring aryl lactones can be synthesized via thelactone arylation procedures substantially similar to those disclosed inMalcolm et al., Tetrahedron Lett., 46: 6871 (2005) to give dichloroanalog 2a and 2b. Opening of lactone 2a/2b with lithium methylamideproceed in excellent yield to give alcohol 3a/3b, which is followed byborane reduction to give amino alcohol 4a/4b. An alternate procedureusing methylamine in ethanol also provides good results in thering-opening step. The procedures are summarized in Scheme 1, below:

Amino alcohol 4a/4b are separated by chiral HPLC (e.g., AD 2:3:95:0.1MeOH/EtOH/Hex/DEA) to give enantiomers 5a/b and 6a/b. Each enantiomer isthen cyclized to provide the corresponding 5-5 and 6-5 bicyclic amines.The methylamine is demethylated using neat 1-chloroethyl chloroformate(CECF) to give 5-5 secondary amines and 6-5 secondary amines. Separationcan be carried out using various methods known in the art. Theprocedures are summarized in Scheme 2, below:

An alternative route to the racemic 6-5 bicyclic des-methyl amine (10,Scheme 3) was also developed that started from lactone 2b. Heatinglactone 2b in the presence of potassium phthalimide provides amino acid7, which can be converted directly to lactam 9 (via intermediate 8)after heating in KOH. Borane reduction of lactam 9 gave the desiredracemic 6-5 desmethyl analog 10.

Racemic 6-5 bicyclic amine 10 can also be separated by chiral HPLC(e.g., Chiracel AD—95:5:0.1 hex/IPA/DEA) to give the correspondingenantiomers (Scheme 4).

6-5 lactone 2b can be also used as the starting point for the synthesisof the N-ethyl substituted analogs (i.e., 13, Scheme 5). Opening of thelactone with ethylamine provides amide-alcohol 11, which is reduced withborane to give amino alcohol 12. Mesylation of 12 and intramolecularcyclization provides racemic N-ethyl product 13.

Racemic 6-5 N-ethyl bicyclic amine 13 can be purified by chiral HPLC(e.g., Chiraltech OD, 95:5:0.05 hex/1PA/DEA) to give the correspondingenantiomers:

5.3 Methods of Treatment, Prevention, and/or Management

5.3.1 Binding to Monoamine Transporter

In various embodiments, provided herein is a method of binding acompound provided herein to a monoamine transporter. The methodcomprises contacting the monoamine transporter and a compound providedherein.

In other embodiments, provided herein is a method of inhibiting bindingof a monoamine transporter ligand to a monoamine transporter (such asserotonin transporter, dopamine transporter and norepinephrinetransporter). The method comprises contacting the monoamine transporterand a compound provided herein. In one embodiment the monoaminetransporter ligand is an endogenous monoamine, such as serotonin,dopamine or norepinephrine. In another embodiment, the ligand is a drugmolecule or another small molecule known to have binding affinity to amonoamine transporter. In another embodiment, the monoamine transporterligand is a radioactively labeled compound, known to bind to themonoamine transporter.

In one embodiment, inhibition of ligand binding is assessed using an exvivo binding assay, such as those described herein. In anotherembodiment, the compound provided herein inhibits mean binding bybetween about 1% and about 100%, between about 10% and about 100%, andbetween about 20% and about 90% when compared to vehicle. In oneembodiment, inhibition of mean binding is dose dependent.

5.3.2 Inhibition of Monoamine Transporter Activity

In various embodiments, provided herein is a method of modulating (e.g.,inhibiting, augmenting) the activity of at least one monoaminetransporter, such as serotonin transporter, dopamine transporter andnorepinephrine transporter. The method comprises contacting themonoamine transporter and a compound provided herein. In one embodiment,the monoamine transporter is contacted with a compound provided hereinby administering to a subject a therapeutically effective amount of thecompound provided herein, or a pharmaceutically acceptable salt orsolvate thereof. The subject may be a human. In another embodiment, themonoamine transporter is dopamine transporter (DAT), serotonintransporter (SERT), or norepinephrine transporter (NET). In otherembodiments, the compound provided herein inhibits the activity of atleast two different monoamine transporters. Inhibition of monoaminetransporter activity may be measured using assays known in the art.Exemplary assay methods include, but are not limited to, in vitrofunctional uptake assays. In one embodiment, the functional uptake assayutilizes an appropriate cell-line expressing a desired monoaminetransporter. In other embodiments, the functional uptake assay utilizessynaptosomes isolated from brain tissue of an appropriate organism. Inother embodiments, inhibition of monoamine transporter activity may beassessed using receptor binding experiments known in the art, e.g.,utilizing appropriate membrane preparations. In one embodiment, theassay involves treatment of a test subject (e.g., a rat) with a compoundprovided herein as well as a reference compound, followed by isolationof brain tissue and ex vivo analysis of receptor occupancy, as describedherein.

5.3.3 Inhibition of Monoamine Uptake

In some embodiments, provided herein is a method of inhibiting uptake ofat least one monoamine (e.g., dopamine, serotonin, norepinephrine) by acell. The method includes contacting the cell with a compound providedherein. In one embodiment, the cell is a brain cell, such as a neuron ora glial cell. In one embodiment, inhibition of monoamine uptake occursin vivo. In an organism, neuronal uptake (also termed reuptake) of amonoamine such as dopamine or serotonin may occur, for example, from thesynaptic cleft. Thus, in one embodiment, the neuronal cell is in contactwith a synaptic cleft of a mammal. In another embodiment, inhibition ofmonoamine uptake occurs in vitro. In some embodiments, the cell may be abrain cell, such as a neuronal cell or a cell-type, which expresses arecombinant monoamine transporter.

In one embodiment, the compound inhibits uptake of at least twodifferent monoamines. This can, for example, be shown by performingvarious in vitro functional uptake assays utilizing a cell-type, whichsimultaneously expresses multiple different monoamine transporters (suchas isolated synaptosomes), or may be shown by using two different celltypes, each expressing a different monoamine transporter, such as arecombinant dopamine transporter, together with an appropriate, labeledmonoamine. In some embodiments, inhibition of monoamine uptake isdemonstrated when the inhibitor (e.g., a compound provided herein) hasan IC₅₀ of, for example, between about 0.1 nM and about 10 μM, betweenabout 1 nM and about 1 μM, between about 1 nM and about 500 nM, andbetween about 1 nM and about 100 nM, in a functional monoamine uptakeassay, such as those described herein below.

5.3.4 Treatment of Neurological Disorders

In some embodiments, provided herein is a method of treating,preventing, and/or managing a neurological disorder. Without beinglimited by a particular theory, the treatment, prevention, and/ormanagement is done by inhibiting the activity of at least one monoaminetransporter. The method comprises administering to a patient (e.g.,human) a therapeutically or prophylactically effective amount of acomposition or compound provided herein, or a pharmaceuticallyacceptable salt or solvate thereof. In one embodiment, the patient is ahuman. In another embodiment, the compound provided herein inhibits theactivity of at least two different monoamine transporters. For example,the compound of the invention inhibits the activity of at least two ofserotonin transporter, dopamine transporter and norepinephrinetransporter. In some embodiments, inhibition of monoamine transporteractivity may be assessed by functional monoamine uptake assays asdescribed herein below.

Demonstration of compound activity can be performed in variousart-recognized animal models. For example, anti-depressant activity of acompound may be assessed by utilizing an appropriate animal model ofdepression such as, but not limited to, the Rat Forced Swim Test, theMouse Tail Suspension Test and Rat Locomotor Activity Analyses. The RatForced Swim Test is also suitable for the analysis of compounds havingactivities against more than one monoamine transporter (mixed monoaminetransporter activity). For example, an increase in swimming activity isindicative of serotonin reuptake inhibition, while an increase inclimbing activity is indicative of norepinephrine reuptake inhibition.

In some embodiments, the compounds provided herein are active in atleast one animal model, which can be used to measure the activity of thecompounds and estimate their efficacy in treating a neuroligal disorder.For example, when the animal model is for depression (e.g., meanimmobility), the compounds are active when they inhibit mean immobilityby between about 5% and about 90%, between about 10% and about 70%,between about 10% and about 50%, and between about 15% and about 50% inat least one animal model, when compared to vehicle. In someembodiments, the compounds provided herein produce a similar disparityin measured endpoint between treated animals and animals administeredvehicle.

In other embodiments, provided herein is a method of effecting ananti-depressant-like effect. The method comprises administering to asubject (e.g., a mammal) a therapeutically effective amount of acompound or composition provided herein, or a pharmaceuticallyacceptable salt or solvate thereof. Anti-depressant-like effects may bemeasured using an animal model of disease, such as those known in theart and those described herein.

In some embodiments, the neurological disorder is: depression (e.g.,major depressive disorder, bipolar disorder, unipolar disorder,dysthymia and seasonal affective disorder); cognitive deficits;fibromyalgia; pain (e.g., neuropathic pain); sleep related disorders(e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including thosesleep disorders which are produced by psychiatric conditions; chronicfatigue syndrome; attention deficit disorder (ADD); attention deficithyperactivity disorder (ADHD); restless leg syndrome; schizophrenia;anxieties (e.g., general anxiety disorder, social anxiety disorder,panic disorder); obsessive compulsive disorder; posttraumatic stressdisorder; seasonal affective disorder (SAD); premenstrual dysphoria;post-menopausal vasomotor symptoms (e.g., hot flashes, night sweats);neurodegenerative disease (e.g., Parkinson's disease, Alzheimer'sdisease and amyotrophic lateral sclerosis); manic conditions; dysthymicdisorder; cyclothymic disorder; obesity; and substance abuse ordependency (e.g., cocaine addiction, nicotine addiction). In anotherembodiment, the compounds provided herein are useful to treat two ormore conditions/disorders, which are comorbid, such as cognitive deficitand depression.

Neurological disorders include cerebral function disorders, includingwithout limitation, senile dementia, Alzheimer's type dementia,cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorders, Lennox syndrome, autism, and hyperkinetic syndrome.

Neuropathic pain includes without limitation post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds, and/or compositionsprovided herein include, but are not limited to: obesity; migraine ormigraine headache; urinary incontinence, including without limitationinvoluntary voiding of urine, dribbling or leakage of urine, stressurinary incontinence (SUI), urge incontinence, urinary exertionalincontinence, reflex incontinence, passive incontinence, and overflowincontinence; and sexual dysfunction, in men or women, including withoutlimitation sexual dysfunction caused by psychological and/orphysiological factors, erectile dysfunction, premature ejaculation,vaginal dryness, lack of sexual excitement, inability to obtain orgasm,and psycho-sexual dysfunction, including without limitation, inhibitedsexual desire, inhibited sexual excitement, inhibited female orgasm,inhibited male orgasm, functional dyspareunia, functional vaginismus,and atypical psychosexual dysfunction.

In one embodiment, the neurological disorder is depression. In anotherembodiment, the neurological disorder is anxiety disorder. In anotherembodiment, the neurological disorder is pain. In another embodiment,the neurological disorder is neuropathic pain. In another embodiment,the neuropathic pain is diabetic neuropathy.

In one embodiment, the neurological disorder is a neurodegenerativedisease. In one embodiment, the neurodegenerative disease is Parkinson'sdisease. In another embodiment, the neurodegenerative disorder isAlzheimer's disease.

In one embodiment, the neurological disorder is incontinence, forexample, urinary incontinence. In another embodiment, the neurologicaldisorder is sexual dysfunction.

In one embodiment, the neurological disorder is obesity, and thetherapeutically effective amount of compound to supply to a patient issufficient so that said patient feels satiated.

In one embodiment, the compounds described herein treat, prevent, and/ormanage a central nervous disorder, without causing addiction to saidcompounds.

Any suitable route of administration can be employed for providing thepatient with a therapeutically or prophylactically effective dose of anactive ingredient. For example, oral, mucosal (e.g., nasal, sublingual,buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular),transdermal, and subcutaneous routes can be employed. Exemplary routesof administration include oral, transdermal, and mucosal. Suitabledosage forms for such routes include, but arc not limited to,transdermal patches, ophthalmic solutions, sprays, and aerosols.Transdermal compositions can also take the form of creams, lotions,and/or emulsions, which can be included in an appropriate adhesive forapplication to the skin or can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose. An exemplary transdermal dosage form is a “reservoir type” or“matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound provided herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. Generally, oral,intravenous, intracerebroventricular and subcutaneous doses of thecompounds provided herein for a patient will range from about 0.005 mgper kilogram to about 5 mg per kilogram of body weight per day. In oneembodiment, the oral dose of a compound provided herein will range fromabout 10 mg to about 300 mg per day. In another embodiment, the oraldose of a compound provided herein will range from about 20 mg to about250 mg per day. In another embodiment, the oral dose of a compoundprovided herein will range from about 100 mg to about 300 mg per day. Inanother embodiment, the oral dose of a compound provided herein willrange from about 10 mg to about 100 mg per day. In another embodiment,the oral dose of a compound provided herein will range from about 25 mgto about 50 mg per day. In another embodiment, the oral dose of acompound provided herein will range from about 50 mg to about 200 mg perday. Each of the above-recited dosage ranges may be formulated as asingle or multiple unit dosage formulations.

In some embodiments, the compounds disclosed herein may be used incombination with one or more second active agents to treat, prevent,and/or manage disorders described herein. Examples of such second activeagents are also provided herein elsewhere.

5.4 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, stereoisomer, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are also disclosed herein.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton, Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose or other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

5.4.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton, Pa. (1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms arc tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form. Disintegrants may be used inthe compositions to provide tablets that disintegrate when exposed to anaqueous environment. Tablets that contain too much disintegrant maydisintegrate in storage, while those that contain too little may notdisintegrate at a desired rate or under the desired conditions. Thus, asufficient amount of disintegrant that is neither too much nor toolittle to detrimentally alter the release of the active ingredients maybe used to form solid oral dosage forms. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. In one embodiment, pharmaceuticalcompositions comprise from about 0.5 to about 15 weight percent ofdisintegrant, or from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

5.4.2 Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art.

Examples include, but are not limited to, those described in U.S. Pat.Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719,5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476,5,354,556, and 5,733,566, each of which is incorporated herein byreference. Such dosage forms can be used to provide slow orcontrolled-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled-releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeagents provided herein. In one embodiment, provided are single unitdosage forms suitable for oral administration such as, but not limitedto, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

5.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

5.4.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton, Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton,Pa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

5.5 Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

6. EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

6.1 Synthesis of Compounds

6.1.1 6a-(3,4-Dichlorophenyl)hexahydro-1H-cyclopenta[c]furan-1-one and7a-(3,4-Dichlorophenyl)hexahydroisobenzofuran-1(3H)-one

2a: To a solution of lactone (hexahydro-1H-cyclopenta[c]furan-1-one, 630mg, 5 mmol), palladium dba (145 mg, 5 mol %) and toluene (6 mL), whichwas stirring under nitrogen in a sealed vial, were addedtri-t-butylphosphine (250 μL, 5 mol %), lithium HMDS (6 mL, 1.2 eq), anddichlorophenylbromide (1.69 g, 1.5 eq). The solution was heated in themicrowave for fifteen minutes (max temp=140° C.). After cooling, themixture was diluted with hexane, washed with 3M HCl, and evaporated. Thecrude brown oil was purified on silica gel to give 2a (578 mg, 44%) as apale-brown oil. TLC R_(f) (25% EA/hex)=0.34. GC-MS R_(t)=12.48 min,m/z=270 (M+). ¹H NMR (CDCl₃, δ): 7.49 (d, J=2.3 Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.24 (dd, J=2.3, 8.4 Hz, 1H), 4.50 (dd, J=7.3, 9.6 Hz, 1H),4.14 (dd, J=2.2, 9.6 Hz, 1H), 3.1 (m, 1H), 2.60 (ddd, J=3.0, 6.4, 12.5Hz, 1H), 2.2-1.6 (m, 5H). ¹³C NMR (CDCl₃, δ, mult): 179.7(0), 140.6(0),132.8(0), 131.5(0), 130.6(1), 128.3(1), 125.8(1), 72.7(2), 59.4(0),46.2(1), 40.3(2), 34.4(2), 25.8(2).

2b: To a flame-dried 250 mL round bottom flask was added Pd(dba)₂ (368mg, 1 mol %) and toluene. The vessel was purged with nitrogen and sealedbefore tri-t-butylphosphine (704 μL, 1M in toluene, 1.1 mol %) was addedvia syringe followed by phenyl bromide (5.4 mL, 51.27 mmol) as asolution in toluene (15 mL). LiHMDS (64 mL, 1.3 eq) was added and thelight brown solution was stirred at ambient temperature for 15 minutes.Hexahydroisobenzofuran-1(3H)-one (10 g, 1.3 eq) was added dropwise as asolution in toluene (20 mL). At this point an exotherm was notedfollowed by the formation of a light colored precipitate. The mixturewas allowed to stir at ambient temperature overnight (16 hours) and thenpartitioned between hexane and, in succession, 10% aqueous HCl, 10%aqueous K₂CO₃, and brine. The volatile components were removed in vacuoto give the crude arylated lactone as a brown-green oil (12.6 g).Separation of the unreacted lactone using a 120 g Redisep cartridge gavethe title compound as a yellow oil (7.40 g, 67%). HPLC R_(t)=9.8 min. ¹HNMR (CDCl₃, δ): 7.4-7.2 (m, 5H), 4.05 (dd, 1H), 3.90 (dd, 1H), 2.8 (m,1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H). ¹³C NMR (CDCl₃, δ,mult): 178.6 (0), 140.5 (0), 128.8 (1), 127.3 (1), 126.3 (1), 70.3 (2),52.5 (0), 41.0 (1), 34.2 (2), 27.5 (2), 23.4 (2), 23.2 (2).

6.1.2 1-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-N-methylcyclopentanecarboxamide and1-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-N-methylcyclohexanecarboxamide

3a: To a solution of methylamine (1.5 mL, 2M in THF, 2 eq) at −78° C.was added n-BuLi (1.2 mL, 2.5M in hexanes, 2 eq) dropwise. After 5minutes, a solution of the 2a (413 mg, 1.529 mmol) in THF (3 mL) wasadded in one portion. The mixture was stirred at low temperature for 5minutes and at ambient temperature for 2 hours. The solution wasquenched with NH₄Cl, extracted with MTBE, and evaporated. The residuewas purified on silica to give methylamide 3a as a pale-yellow oil(351.0 mg, 76%). TLC R_(f) (50% EA/hex)=0.13. GC-MS R_(t)=12.4 min,m/z=283 (M−H₂O). ¹H NMR (CDCl₃, δ): 7.51 (d, J=2.3 Hz, 1H), 7.40 (d,J=8.5 Hz, 1H), 7.25 (dd, J=2.3, 8.5 Hz, 1H), 3.8 (bs, 1H), 3.7 (m, 2H),3.5 (s, 1H), 2.73 (d, J=4.8 Hz, 3H), 2.7-2.4 (m, 2H), 2.1-1.5 (m, 5H).¹³C NMR (CDCl₃, δ, mult): 175.7(0), 144.4(0), 132.5(0), 131.0(0),130.4(1), 129.1(1), 126.8(1), 63.9(2), 61.3(0), 50.0(1), 37.9(2),27.8(2), 26.7(3), 22.1(2).

Using similar procedures, 3b was also made from 2b.

6.1.3(2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclopentyl)methanol and(2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclohexyl)methanol

4a: To a solution of amide 3a (110 mg, 0.4412 mmol) in THF (1.3 mL) wasadded borane-THF (1.3 mL). After two minutes, the solution was heated inthe microwave for 30 minutes (max temp=100° C.). After cooling, thereaction was quenched cautiously with a few drops of methanol followedby 3N HCl (4 mL) and stirred for 30 minutes. The solution was washedwith 50%MTBE/hexanes, chilled, basified with KOH, and extracted withMTBE. After evaporation, the compound was filtered through anaminopropyl cartridge to give amine 4a (315.9 mg, 95% yield) as apale-yellow oil. LCMS (14 min) R_(t)=5.98 min, m/z=288 (M+1). ¹H NMR(CDCl₃, δ): 7.6 (m, 1H), 7.4 (m, 2H), 6.8 (bs, 1H), 3.7 (m, 2H), 2.8 (m,3H), 2.32 (s, 3H), 2.1-1.2 (m, 6H). ¹³C NMR (CDCl₃, δ, mult): 147.3(0),132.5(0), 130.2(1), 130.1(1), 129.3(0), 126.9(1), 63.7(2), 58.3(2),52.9(0), 47.1(1), 41.6(2), 36.0(3), 28.6(2), 22.1(2).

Using similar procedures, 4b was made from 3b.

6.1.4((1R,2S)-2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclopentyl)methanol(5a),((1R,2S)-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexyl)methanol(6a),((1S,2R)-2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclopentyl)methanol(5b), and((1S,2R)-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexyl)methanol

Compounds 4a was separated by chiral HPLC (AD-2:3:95:0.1MeOH/EtOH/Hex/DEA) to provide the products 5a and 6a. Using similarprocedures, compound 4b was separated into compounds 5b and 6b.

6.1.5(3aS,6aR)-3a-(3,4-Dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrroleand (3aR,6aS)-3a-(3,4-Dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole

Amino 15a (47.3 mg, 0.164 mmol) was dissolved in 1 mL DCM and allowed toreact with mesyl chloride (19 μL, 1.5 eq) in the presence ofdiisopropylethylamine (86 μL, 3 eq) for two hours. The mixture wasquenched with aqueous potassium carbonate and extracted with MTBE. Thecrude residue after evaporation was passed through an aminopropyl columnto provide(3aS,6aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole(43.5 mg, 99%) as a clear oil. LCMS R_(t)=8.56 min m/z=270 (M+1). ¹H NMR(CDCl₃, δ): 7.41 (d, J=2.3 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.17 (dd,J=2.3, 8.4 Hz, 1H), 2.87 (t, J=8.4 Hz, 1H), 2.7 (m, 1H), 2.6 (m, 2H),2.3 (m, 1H), 2.32 (s, 3H), 2.0-1.5 (m, 6H). ¹³C NMR (CDCl₃, δ, mult):150.4(0), 131.9(0), 129.9(1), 128.2(1), 125.7(1), 70.4(2), 64.6(2),58.3(0), 50.2(1), 42.0(3), 41.0(2), 33.6(2), 25.8(2).

(3 aR,6aS)-3a-(3,4-Dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole was alsomade using similar procedures, and using amino 16a as a startingcompound.

6.1.6 (3aS,6aR)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole and(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole

(3aS,6aR)-3a-(3,4-Dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole(20 mg) was dissolved in 1-chloroethyl chloroformate (250 μL) and heatedto 80° C. for 15 hours. The reaction was cooled and evaporated. Theresidue was dissolved in methanol and heated at 80° C. for an additional3 hours. After evaporation, the residue was diluted in DCM, washed withK₂CO₃, and filtered (aminopropyl cartridge).(3aS,6aR)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole was thenseparated from unreacted starting material by chromatography (ChiracelAD; 95:5:0.1 IPA/Hex/DEA). LCMS R_(t)=7.14 min m/z=256 (M+1). ¹H NMR(CDCl₃, δ): 7.3 (m, 2H), 7.12 (dd, J=2.3, 8.4 Hz, 1H), 3.3 (m, 1H), 3.00(s, 2H), 2.7 (m, 2H), 2.0-1.9 (m, 3H), 1.8-1.5 (m, 2H), 1.5 (m, 1H). ¹³CNMR (CDCl₃, δ, mult): 150.2(0), 132.1(0), 130.0(1), 129.4(0), 128.1(1),125.7(1), 62.2(2), 60.0(0), 56.1(2), 50.7(1), 40.5(2), 33.7(2), 25.8(2).

(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole was madeusing similar procedures, using(3aR,6aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrroleas a starting compound.

6.1.7 (3aS,7aR)-3a-(3,4-Dichlorophenyl)-2-methyloctahydro-1H-isoindoleand (3 aR,7aS)-3a-(3,4-Dichlorophenyl)-2-methyloctahydro-1H-isoindole

Amino alcohol 5b (40 mg, 0.1323 mmol) was dissolved in DCM (1 mL) andstirred at ambient temperature. To this solution was added DIPEA (70 μL,3 eq) and MSCl (15 μL, 1.5 eq). After 2 hours, the reaction was quenchedwith potassium carbonate and extracted with MTBE. The organic phase wasseparated and evaporated. The residue was dissolved in DCM, filtered(aminopropyl) and evaporated to give(3aS,7aR)-3a-(3,4-Dichlorophenyl)-2-methyloctahydro-1H-isoindole (28.3mg, 75%) as a clear oil. LCMS R_(t)=8.20 min, m/z=284 (M+1). ¹H NMR(CDCl₃, δ): 7.43 (d, J=2.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.19 (dd,J=2.3, 8.5 Hz, 1H), 2.9 (m, 2H), 2.78 (t, J=9.2 Hz, 1H), 2.7-2.6 (m,2H), 2.42 (s, 3H), 2.0-1.8 (m, 2H), 1.8-1.6 (m, 2H), 1.6-1.4 (m, 3H),1.2-1.0 (m, 1H). ¹³C NMR (CDCl₃, δ, mult): 146.9(0), 132.2(0), 130.1(1),129.8(0), 128.8(1), 126.1(1), 69.8(2), 58.8(2), 47.7(0), 43.3(3),40.5(1), 34.3(2), 24.6(2), 21.7(2), 20.9(2).

(3aR,7aS)-3a-(3,4-Dichlorophenyl)-2-methyloctahydro-1H-isoindole wasprepared using similar procedures, and using amino alcohol 6b as astarting compound.

6.1.8 7a-(3,4-Dichlorophenyl)octahydro-1H-isoindol-1-one

A mixture of dichlorophenyl lactone 2b (580 mg, 2.049 mmol), potassiumphthalimide (758 mg, 2 eq), and DMF (4 mL) was stirred in a 150° C. bathfor 24 hours. Evaporation gave the crude acid. The crude material fromabove was diluted with 5M KOH (10 mL) and heated in a 110° C. bath for24 hours. Extraction with ethyl acetate followed by evaporation gave thecrude lactam. Separation on silica gel gave pure7a-(3,4-dichlorophenyl)octahydro-1H-isoindol-1-one (67.5 mg, 12%) as aclear oil. TLC R_(f) (50% EA/hex)=0.25. GC-MS R_(t)=13.77 min, m/z=283(M−1). LCMS R_(t)=9.09 min. HPLC R_(t)=10.15 min. ¹H NMR (CDCl₃/DMSO-D6,δ): 7.37 (d, J=2.3 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.14 (dd, J=2.3, 8.5Hz, 1H), 4.02 (s, 1H), 3.07 (dd, J=5.8, 9.9 Hz, 1H), 2.83 (dd, J=3.6,9.9 Hz, 1H), 2.6 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H), 1.6-1.2 (m, 6H). ¹³CNMR (CDCl₃/DMSO-D6, δ, mult): 179.3(0), 142.5(0), 132.2(0), 130.6(0),130.1(1), 128.8(1), 126.2(1), 51.6(0), 44.2(2), 40.3(1), 32.6(2),26.9(2), 22.7(2), 22.6(2).

6.1.9 3a-(3,4-Dichlorophenyl)octahydro-1H-isoindole

7a-(3,4-Dichlorophenyl)octahydro-1H-isoindol-1-one (65 mg, 0.2287 mmol)was diluted in THF (2 mL) and borane (0.7 mL, 1 M in THF, 3 eq) andheated in the microwave for 15 minutes (max temp=100° C.). Aftercooling, the mixture was stirred with 6N HCl for thirty minutes andwashed with MTBE. The aqueous layer was basicified with KOH andextracted with MTBE. The organic phase was evaporated and filtered(aminopropyl cartridge) to give3a-(3,4-dichlorophenyl)octahydro-1H-isoindole (15.5 mg, 24%) as a clearoil. A further portion was later found in the organic wash and separatedby silica gel filtration to give 19 mg (26%) additional product. LCMSR_(t)=7.60 min, m/z=270 (M+1). ¹H NMR (CDCl₃, δ): 7.43 (d, J=2.3 Hz,1H), 7.37 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.3, 8.5 Hz, 1H), 3.1 (m, 2H),2.9 (m, 1H), 2.6 (m, 2H), 2.0-1.2 (m, 8H). ¹³C NMR (CDCl₃, δ, mult):146.7(0), 132.3(0), 130.1(1), 129.7(0), 128.9(1), 126.2(1), 59.9(2),49.6(2), 47.9(0), 41.0(1), 32.8(2), 24.2(2), 22.0(2), 21.4(2).

Racemic 3a-(3,4-dichlorophenyl)octahydro-1H-isoindole was separated bychiral HPLC (Chiracel AD-95:5:0.1 Hex/IPA/DEA) to provide the isomers(3aS,7aR)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole and(3aR,7aS)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole:

6.2 Monoamine Reuptake Assays

The compounds disclosed herein were tested for their inhibition offunctional uptake of serotonin (5-HT), norepinephrine (NE), and dopamine(DA), using recombinant human transporters, as described herein below.Compounds were initially tested at 10 μM in duplicate. Compounds showingequal to or higher than 50% inhibition of uptake were further tested at10 different concentrations in duplicate in order to obtain fullinhibition curves. IC₅₀ values (concentration inhibiting controlactivity by 50%) were then determined by nonlinear regression analysisof the inhibition curves.

6.2.1 Serotonin Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human serotonin reuptake transporter was assayed using therecombinant human serotonin transporter expressed in HEK-293 cells usinga method substantially similar to that described in Gu H et al., J.Biol. Chem. 1994, 269 (10): 7124-7130, incorporated herein by reference.HEK-293 cells expressing human serotonin transporter were plated beforethe assay. Test compound and/or vehicle was preincubated with cells inmodified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C.,and 65 nM [³H]serotonin was then added for an additional timedincubation period (ten to thirty minutes). Cells with internalized[³H]serotonin were washed, and the amount of tritium taken into cells iscounted using a liquid scintillation counter to determine [³H]serotoninuptake. Non-specific binding of tritium was measured in a controlreaction containing 10 μM fluoxetine, and was subtracted from the countsfor assays to correct for non-specific binding of tritium. Reduction of[³H]serotonin uptake by 50 percent or more relative to an uninhibitedcontrol reaction indicates significant inhibitory activity. Compoundswere screened at 10, 1, 0.1, 0.01 and 0.001 μM.

6.2.2 Norepinephrine Functional Uptake Assay for Human ReuptakeTransporter

Inhibition of human norepinephrine reuptake transporter was assayedusing the recombinant human norepinephrine transporter expressed ineither HEK293 or MDCK cells using a method substantially similar to thatdescribed in Galli A et al., J. Exp. Biol. 198: 2197-2212 (1995),incorporated herein by reference. The cells were plated before theassay. Test compound and/or vehicle was preincubated with cells inmodified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C.Following the preincubation, 25 nM [³H]norepinephrine was added for anadditional timed incubation period (10 to 20 minutes). After the cellswere washed to remove [³H]norepinephrine not internalized, the cellswere lysed, and the amount of tritium in the cell lysate was measuredusing a liquid scintillation counter to determine [³H]norepinephrineuptake. Non-specific binding of tritium was measured in a controlreaction containing 10 μM imipramine (or 10 μM nisoxetine), and wassubtracted from the counts for assays to correct for non-specificbinding of tritium. Reduction of [³H]norepinephrine uptake by 50 percentor more relative to an uninhibited control reaction indicatessignificant inhibitory activity. Compounds were screened at 10, 1, 0.1,0.01 and 0.001 μM.

6.2.3 Dopamine Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human dopamine reuptake transporter was assayed using therecombinant human dopamine transporter expressed in either CHO-K1 orHEK293 cells using a method substantially similar to that described inPristupa, Z. B. et al., Mol. Pharmacol. 45: 125-135 (1994), incorporatedherein by reference. Either CHO-K1 or HEK293 cells expressing humanrecombinant dopamine transporter were plated before the assay. Testcompound and/or vehicle was preincubated with cells in modified HEPESbuffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C., and 50 nM[³H]dopamine was then added for an additional timed incubation period(10 to 30 minutes). After washing the cells to remove [³H]dopamine notinternalized, the cells were lysed, and the amount of tritium in thelysate was measured using a liquid scintillation counter to determine[³H]dopamine uptake. Non-specific binding of tritium was measured in acontrol reaction containing 10 μM nomifensine, and was subtracted fromthe counts for assays to correct for non-specific binding of tritium.Reduction of [³H]dopamine uptake by 50 percent or more relative to anuninhibited control reaction indicates significant inhibitory activity.Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM.

6.2.4 Results

6.2.4.1 Serotonin Uptake Inhibition Certain compounds provided hereinwere tested for serotonin reuptake inhibition using the proceduresdescribed in Section 6.2.1 above. Tested compounds included:(3aS,6aR)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aS,6aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aS,7aR)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole; (3aR,7aS)-3 a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole; and (3aS,7aR)-3 a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole. The IC₅₀values obtained from these compounds ranged from 3 to 551 nM.

6.2.4.2 Norepinephrine Uptake Inhibition

Certain compounds provided herein were tested for norepinephrinereuptake inhibition using the procedures described in Section 6.2.2above. Tested compounds included:(3aS,6aR)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aS,6aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aS,7aR)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole; and(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole. TheIC₅₀ values obtained from these compounds ranged from 13 to 212 nM.

6.2.4.3 Dopamine Uptake Inhibition

Certain compounds provided herein were tested for serotonin reuptakeinhibition using the procedures described in Section 6.2.3 above. Testedcompounds included:(3aS,6aR)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aS,6aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aS,7aR)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole; and(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole. TheIC₅₀ values obtained from these compounds ranged from 7 to 254 nM.

6.3 Metabolic Stability

The liver is the main organ of drug metabolism in the body. Certaincompounds provided herein were tested for microsomal stability using thefollowing procedures:

Subcellular fractions such as liver microsomes arc useful in vitromodels of hepatic clearance. The human or mouse microsomes wereincubated with the test compounds at 37° C. in the presence of theco-factor, NADPH, which initiated the reaction. The reaction wasterminated by the addition of methanol. Following centrifugation, thesupernatant was analyzed on the LC-MS/MS. The disappearance of testcompound was monitored over a 45 minute time period.

Tested compounds included:(3aS,6aR)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole;(3aS,6aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aR,6aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole;(3aS,7aR)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)octahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-methyloctahydro-1H-isoindole;(3aR,7aS)-3a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole; and(3aS,7aR)-3a-(3,4-dichlorophenyl)-2-ethyloctahydro-1H-isoindole. Thehalf-lives ranged from 22 to 262 minutes and 8 to 91 minutes in humanand mouse liver microsomes, respectively.

6.4 Pain Models

Effects of(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole on acuteand persistent inflammatory pain were evaluated in male rats. Pain wasinduced experimentally by application of a chemical irritant, formalin,which results in a biphasic behavioral response that includes both early(Phase 1, 0-9 minutes) and late (Phase 2, 10-60 minutes) phase flinchingbehavior. The early phase response is considered to be the result ofC-fiber activation while the late phase appears to be dependent on thecombination of an inflammatory response in the tissue and functionalchanges in the dorsal horn of the spinal cord.

6.4.1 Procedures

Male rats (Sprague-Dawley, 272-315 g, Harlan) were housed 4 animals percage in a temperature-controlled environment on a 12-hour light-darkcycle with food and water available ad libitum. Animals were allowed toacclimate to the facility for at least 5 days before testing. On the dayof the study, a flexible, light-weight, ‘C’-shaped metal band wasapplied to one hind paw and the rat was dosed orally (PO, 3 mL/kg, viagavage) or intraperitoneally (IP, 1 mL/kg) with vehicle (50 mM acetatebuffer (pH 4.5)),(3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole orgabapentin.(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole wasadministered at 3, 10 and 30 mg/kg PO in 50 mM acetate buffer (pH 4.5)vehicle. Gabapentin (AvaChem Scientific) was administered at 100 mg/kgIP in saline vehicle as a positive control. Sixty minutes after compoundadministration, animals were administered a dilute formalin solution(5%, 50 μL) into the dorsal aspect of the hind paw with the ‘C’-shapedmetal band and then immediately placed in individual test cylinders(Automated Nociception Analyzer, UCSD, San Diego, Calif.).Formalin-induced flinching behavior was recorded for 60 minutes.

6.4.2 Results

Formalin administration resulted in a biphasic flinch response, in whichthe sum of behavior was greater in phase II (10-60 minutes postformalin) compared to phase I (0-9 minutes post formalin).(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrroleadministration resulted in a significant, dose-related decrease inflinching behavior during phases I and II. Gabapentin administrationresulted in a significant and selective attenuation of phase IIformalin-induced flinching behavior.

As shown in FIG. 3, acute oral administration of(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrolesignificantly and dose-dependently attenuated formalin-induced flinchingbehavior in a non-selective manner when tested in naïve male rats up to30 mg/kg. The robustness of the assay was confirmed by the significantand selective attenuation of phase II formalin-induced flinchingbehavior by the positive control, gabapentin. These results indicatethat (3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrroleeffectively reduced acute and persistent inflammatory pain in rats and,thus, indicates the compound's potential efficacy in relieving pain.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to this application. Thefull scope of the disclosure is better understood with reference to theappended claims.

1-28. (canceled)
 29. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: m is 1 or 2; n is 1; X is hydrogen or (C₁-C₁₀)alkyl; and Y andZ are each independently halogen.
 30. The compound of claim 29, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is
 1. 31. The compound of claim 30, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein X ishydrogen.
 32. The compound of claim 31 or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein Y and Z are bothchloride.
 33. The compound of claim 30, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein X is (C₁-C₁₀)alkyl. 34.The compound of claim 33, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein Y and Z are both chloride. 35.The compound of claim 34, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein X is methyl or ethyl.
 36. Amethod of inhibiting the activity of at least one monoamine transporter,the method comprising contacting the monoamine transporter and acompound of claim 30, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein the monoamine transporter is a serotonintransporter (SERT), a dopamine transporter (DAT), a norepinephrinetransporter (NET), or a combination thereof.
 37. A method of treating acentral nervous system disorder in a patient, the method comprisingadministering to the patient a therapeutically effective amount of acompound of claim 30, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein the central nervous system disorder isdepression, cognitive deficit, fibromyalgia, pain, sleep disorder,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless leg syndrome, schizophrenia, anxiety,obsessive compulsive disorder, posttraumatic stress disorder,premenstrual dysphoria, or a neurodegenerative disease.
 38. The methodof claim 37, wherein the central nervous system disorder is depression.39. The method of claim 37, wherein the central nervous system disorderis attention deficit disorder (ADD) or attention deficit hyperactivitydisorder (ADHD).
 40. The compound of claim 29, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is
 2. 41.The compound of claim 40, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein X is hydrogen.
 42. Thecompound of claim 41 or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Y and Z are both chloride.
 43. Thecompound of claim 42, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is (C₁-C₁₀)alkyl.
 44. The compound ofclaim 43, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Y and Z are both chloride.
 45. Thecompound of claim 44, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein X is methyl or ethyl.
 46. A method ofinhibiting the activity of at least one monoamine transporter, themethod comprising contacting the monoamine transporter and a compound ofclaim 40, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein the monoamine transporter is a serotonintransporter (SERT), a dopamine transporter (DAT), a norepinephrinetransporter (NET), or a combination thereof.
 47. A method of treating acentral nervous system disorder in a patient, the method comprisingadministering to the patient a therapeutically effective amount of acompound of claim 40, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein the central nervous system disorder isdepression, cognitive deficit, fibromyalgia, pain, sleep disorder,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless leg syndrome, schizophrenia, anxiety,obsessive compulsive disorder, posttraumatic stress disorder,premenstrual dysphoria, or a neurodegenerative disease.
 48. The methodof claim 47, wherein the central nervous system disorder is depression.49. The method of claim 47, wherein the central nervous system disorderis attention deficit disorder (ADD) or attention deficit hyperactivitydisorder (ADHD).